Synthesis and in vitro inhibitory activities of dual COX/5-LOX inhibitor 1,5-diarylpyrazole-3-propanoic acid derivatives

Drugs are able to inhibit cyclooxygenase (COX) and 5-lipoxygenase (5-LOX)enzymes, two major pathways of arachidonic acid metabolism, are thought to havepowerful anti-inflammatory activity as well as better tolerability with respect togastrointestinal and cardiovascular safety. Based on this therapeutic approach, theaim of this study was to obtain compounds with dual COX and 5-LOX inhibitoryactivities, which can be used as leads for design of novel anti-inflammatory drugs. Forthis purpose, three groups of 1,5-diarylpyrazol-3-propanoic acid derivativescharacterized by the presence of chloropyridazine, methoxypyridazine andpyridazinone rings at 1-position of the pyrazole nucleus were prepared. This seriesalso included differently substituted phenyl ring at 5 position of pyrazole. In addition,one derivative with sulfonylmethylpyridazine and nonsubstituted phenyl rings aboutthe central pyrazole was prepared. The structures of thirty newly synthesizedcompounds were fully elucidated using spectral techniques and elemental analysis.The obtained twenty-six final compounds reported herein were evaluated fortheir ability to inhibit COX and 5-LOX enzymes. IC50 values for 3-[1-(6-chloropyridazin-3-yl)-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]propanoic acid (2g) were determinedas 1.5 ?M and 1.6 ?M for COX-1 and COX-2, respectively. In addition, in the sameseries, compounds 2b (4-fluorophenyl derivative) and 2f (4-methylphenyl derivative)inhibited 5-LOX product synthesis with IC50 values 12 ?M and 14 ?M, respectively.Molecular modeling studies were also carried out to further investigate the predictedbinding modes of the active compounds with enzymes active site.In summary, the preliminary in vitro activity results of this class of compounds(especially compounds 2b, 2f and 2g) may possess potential for further studies todevelop dual inhibitors of COX/5-LOX.